The United States Food and Drug Administration (FDA) typically evaluates a drug or a device prior to approving or rejecting it for human consumption or use. The FDA approval process involves determining the safety and effectiveness of the drug or the device in question by reviewing data from clinical trials, in which the drug or device is administered under controlled conditions. Clinical trials often begin with a single study that includes a small number of subjects located at one testing facility, and then gradually progress to include many studies of increasingly larger numbers of subjects located at numerous, geographically dispersed, testing facilities. The entity seeking drug or device approval compiles the data from these trials and then submits the data via direct delivery, mail, fax, email, and data uploads, PDF, etc., to the FDA for review.
The FDA only considers data that are identical in nature to the original data, which are recorded in what is known as source documents. All other transcriptions, iterations, compilations, analyses and interpretations of the data are derived from and are dependent upon the data as they were originally recorded in the source documents, which traditionally have been hand written.
Those of skill in the pertinent arts will readily appreciate that the FDA's acceptance of data from clinical trials for decision-making purposes depends primarily upon the authenticity, quality, and integrity of the original data which the FDA determines during on-site inspections and audits, the results of which it compares with the data that the sponsor has submitted to the FDA in support of its new drug application.
Recent federal regulations and FDA guidance documents have provided for the existence of electronic source documents and have defined significant terminology and requirements for electronic source documents. For example, a recent FDA article entitled Guidance for Industry: Computerized Systems Used in Clinical Investigations, U.S. Department of Health and Human Services, Food and Drug Administration, Office of the Commissioner (May 2007), “ . . . provides to sponsors, contract research organizations (CROs), data management centers, clinical investigators, and institutional review boards (IRBs), recommendations regarding the use of computerized systems in clinical investigations. The computerized system applies to records in electronic form that are used to create, modify, maintain, archive, retrieve, or transmit clinical data required to be maintained, or submitted to the FDA.” The source data are necessary for the reconstruction and evaluation of the study to determine the safety of, for example, food and color additives, or the safety and effectiveness of new human and animal drugs, and medical devices; consequently, this guidance is intended to assist in ensuring confidence in the reliability, quality, and integrity of electronic source data and source documentation (i.e., electronic records). Id. at p. 1, q.v.
This same guidance document provides an abbreviated list of definitions of terms commonly used in FDA guidance documents in this context:                An audit trail is a process that captures details such as additions, deletions, or alterations of information in an electronic record without altering the original record. An audit trail facilitates the reconstruction of the course of such details relating to the electronic record.        A certified copy is a copy of original information that has been verified, as indicated by a dated signature, as an exact copy having all of the same attributes and information as the original.        A computerized system includes computer hardware, software, and associated documents (e.g., a user manual) that create, modify, maintain, archive, retrieve, or transmit in digital form information related to the conduct of a clinical trial.        Direct entry is a method of recording data wherein an electronic record is the original means of capturing the data. Examples include the keystroke entry of original observations into a system by an individual, an automatic recording generated by a scale that measures a subject's body weight, etc.        An electronic record is any combination of text, graphics, data, audio, video, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.        Original data are those values that represent a first recording of study data. The FDA currently allows original documents and the original data recorded on those documents to be replaced by copies, provided the copies are identical and have been verified as such.        Original documents and records include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in a clinical trial.        Transmit is a method of transferring data within or among clinical study sites, contract research organizations, data management centers, sponsors, or to the FDA.        
Id. at p. 8.
In order to prevent fraud when investigators and sponsors have access to the same system, a clinical investigator must retain records required to be maintained for a particular period of time as specified in the relevant regulation. This requirement applies to the retention of the original source document, or a copy of the source document. When source data are transmitted from one system to another (e.g., from a personal data assistant to a sponsor's server), or entered directly into a remote computerized system (e.g., data are entered into a remote server via a computer terminal that is located at the clinical site), or an electrocardiogram at the clinical site is transmitted to the sponsor's computerized system, a copy of the data should be maintained at another location, typically at the clinical site but possibly at some other designated site. Copies should be made contemporaneously with data entry and should be preserved in an appropriate format, such as XML, PDF or paper formats.
The FDA considers ‘original data’ to be “those values that represent the first recording of study data.” Id. at p. 8. “When original observations are entered directly into a computerized system, the electronic record is called the source document.” Id. at p. 4.
Ideally, a system would exist that would admit to direct entry of all the original data of a clinical trial into a single computerized system, the electronic record of which would reside in one location, in one database. The electronic record would include an audit trail that captures any and all details such as additions, deletions, or alterations of information in the electronic record without obliterating the original record. This electronic record would be the clinical trial source document, and it would be available for entry or review in real-time from even remote locations. For example, the electronic source document, in such an ideal system, would enable the sharing of original data, in their original forms, within or among clinical study sites, contract research organizations, data management centers, the sponsoring organization, institutional review boards, or the FDA. Data transcriptions, case report forms, the transfer of data between and among servers would no longer be necessary. Further, the need for copies made contemporaneously with data entry and preserved in a format such as XML, PDF or paper may also become obsolete.
This ideal approach is not, however, currently utilized in any known system. To the contrary, source documents in clinical trials tend to be heterogeneous documents maintained in decentralized locations and primarily recorded on paper. Even in medical offices that use electronic medical records systems (EMR's), these EMR's are typically not suitable for use as the source documents for clinical trials: they lack the structure and means to accommodate both patient and clinical trials data together in a single system, do not fulfill all the requirements associated with sponsor designs, regulatory guidelines and requirements, etc., and are usually compilations of documents, transcriptions, dictation uploads, and other entries that are not original in nature.
The documents for a clinical trial are created by, and reside at the disparate and unconnected locations of, the assortment of principals involved in the various parts of the clinical trial. The principals who create and/or review clinical trial data include a sponsoring organization, such as a pharmaceutical company or other party interested in the approval of a medicine or device (“sponsor”), whose application to the FDA for the approval of its drug or device includes the submission of protocols and study plans (e.g., requirements, procedures, schedules) for the clinical trials; a plurality of clinical investigators (“investigators”), who recruit subject patients that meet the clinical trials requirements, gather and record their medical history information (e.g., illnesses, conditions, medications, operations, medication allergies, etc.) before, during, and at the conclusion of the trial, interpret the clinical trial study plan and then perform the study visits and procedures on the subject patients, including the administration of the test drug or device and documenting the subject patients' responses to it; an ethical or institutional review board (“IRB”), that monitors the activities of the sponsor and the investigator sites to protect subject rights and safety; and the miscellaneous other providers of services and supplies (“vendors”), such as the manufacturer and shipper of the test agent and the clinical and analytical laboratories that analyze subject samples.
Currently, the source documents themselves are not submitted to the sponsor by the investigators, the IRB, or the vendors. Instead, each entity extracts whatever original data elements are required by the protocol and then submits transcriptions of the data elements by using either paper or electronic proxies for the original data. For example, the sponsor usually requires that the investigators transcribe data from the source documents to paper or electronic forms, called case report forms. The data contained in these case report forms, in turn, comprise a centralized repository for the proxy data. The sponsor analyzes the proxy data and then submits PDF versions of the case report forms, copies of the centralized proxy data repository, and its analyses of the data to the FDA. Since the case report forms, the central proxy data repository, and the PDF forms are not the original data, however, the Sponsor and the FDA must verify the proxy data against the original data, and they also must determine whether the original data are true, accurate, authentic, and in compliance with the requirements of the protocol, by viewing the actual source documents at the various locations where the source documents physically reside.
These sponsor and FDA on-site reviews of the source documents often reveal errors and discrepancies among the clinical trial protocol and study plan requirements; the investigators' interpretations of the study protocol and its study plan and procedures; the procedures actually performed; the types and formats of data gathered during the trial; the source document data; the case report form (proxy) data; the sponsor's intermediate and final databases; and the data and documents reviewed by the FDA. These findings often lead to the invalidation of some or all of the clinical trial data.
Currently, the sponsor, depending upon the size and duration of a particular clinical trial, typically is able to send site monitors to perform its reviews of the source documents at the investigator sites only at the conclusion of a trial and periodically during the trial, usually no more frequently than every six weeks. This means that significant findings of protocol non-compliance, subject safety issues, errors and omissions in source documentation, and discrepancies between the original data in the source documents and the proxy data in the paper or electronic case report forms may go unidentified for weeks or months; or that identification of data patterns that might suggest a need to revise the protocol for safety or scientific reasons are too late to be actionable.
Currently, the FDA typically reviews source documents only after the clinical trials are completed and after the sponsor has submitted the resulting data to the FDA. Further, the FDA does not have the resources to visit every geographically dispersed testing facility. With the increasing number of domestic and global facilities and international studies taking place, the FDA usually only selects a limited number of facilities to inspect following completion of clinical trials, so that most clinical trial source data has not yet been verified by the FDA before a drug or device for human consumption or use is approved.
Thus, current clinical data systems waste time and resources at each step in the drug development, testing and approval process; place study data integrity and study patient subjects at risk; potentially endanger wider patient populations who become exposed to the drug or device after it has been approved following inadequate regulatory review of clinical trial source documents; and preclude timely and strategic decision-making by sponsors, IRBs, and the FDA in the drug development, testing, and approval processes.
Recent attempts to centralize the proxy data by electronic means include filters and prompts at both the decentralized site computers and at an intermediary information center database in order to facilitate “cleaning” the data (reconciliation of discrepancies between original data and proxy data), before the proxy data are uploaded to a final database for final analysis and then submission to the FDA. While these features are intended to improve the quality of proxy data, they would be out of place in a system that centralizes original data, since the imposition of intermediary feedback signaling and filtering systems would introduce the possibility of biasing the data and invalidating the process of collecting true and original observations in the form of original data as recorded in an electronic source document.
There is therefore, a long-felt but unmet need for a secure and reliable electronic source document generation and storage process in which medical history and clinical trial data can be recorded and verified in a globally consistent manner. Likewise, as electronic document systems expand more generally (e.g., government mandated electronic medical records, electronic prescriptions, insurance processing, etc.), there will be an ongoing need for secure and reliable electronic source documents in which data can be recorded, verified, and shared among authorized entities (e.g., the patient, the patient's health care providers, regulators, etc.) in a manner consistent with the requirements of such programs. The availability of such a centralized electronic source document system will also help meet the ongoing needs to facilitate the recruitment of subjects for clinical trials; patients' locating studies in which they might want to participate; the evaluation of the relative benefits of different treatment regimens in large populations for planning improved treatment and drug development programs for better health outcomes; and capturing medical conditions for the FDA Adverse Event Reporting System (AERS) by tracking subjects' medical histories not only during but also after they complete trials.